EP1371647B1 - Pyridin-3-carbonsäurederivate und ihre Verwendung als Zwischenprodukte - Google Patents
Pyridin-3-carbonsäurederivate und ihre Verwendung als Zwischenprodukte Download PDFInfo
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- EP1371647B1 EP1371647B1 EP03013988A EP03013988A EP1371647B1 EP 1371647 B1 EP1371647 B1 EP 1371647B1 EP 03013988 A EP03013988 A EP 03013988A EP 03013988 A EP03013988 A EP 03013988A EP 1371647 B1 EP1371647 B1 EP 1371647B1
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- Prior art keywords
- title compound
- preparation
- pyridin
- ylsulphonyl
- dichloromethane
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- 0 *c1n[n](*)c2c1N=C(c1c(*)ncc(*)c1)NC2=O Chemical compound *c1n[n](*)c2c1N=C(c1c(*)ncc(*)c1)NC2=O 0.000 description 5
- AHPWULFANUCOGZ-UHFFFAOYSA-N CCC(COC)Oc(c(C(N1)=Nc2c(CC)[n](C)nc2C1=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O Chemical compound CCC(COC)Oc(c(C(N1)=Nc2c(CC)[n](C)nc2C1=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O AHPWULFANUCOGZ-UHFFFAOYSA-N 0.000 description 2
- KUHBRIURQYAIJF-UHFFFAOYSA-N CCCCOc(c(C(N1)=Nc2c(CC)[n](CC3N=NC=CC3C)nc2C1=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O Chemical compound CCCCOc(c(C(N1)=Nc2c(CC)[n](CC3N=NC=CC3C)nc2C1=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O KUHBRIURQYAIJF-UHFFFAOYSA-N 0.000 description 1
- FYYVSZHPDZDAOS-UHFFFAOYSA-N CCCNc(c(C(Nc1c(CC)[n](Cc2ccccn2)nc1C(N)=O)=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O Chemical compound CCCNc(c(C(Nc1c(CC)[n](Cc2ccccn2)nc1C(N)=O)=O)c1)ncc1S(N1CCN(CC)CC1)(=O)=O FYYVSZHPDZDAOS-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3',5'-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds of the invention are potent and selective inhibitors of type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE5) and have utility therefore in a variety of therapeutic areas.
- the compounds are of value in the treatment of male erectile dysfunction (MED) and female sexual dysfunction (FSD) but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated.
- Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g.
- post-PTCA post-percutaneous transluminal coronary angioplasty
- peripheral vascular disease stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
- IBS irritable bowel syndrome
- pre-eclampsia Kawasaki's syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction.
- Particularly preferred conditions include MED and FSD.
- alkyl, alkoxy and alkenyl groups having three or more carbon atoms, and alkanoyl groups having four or more carbon atoms may be straight chain or branched chain.
- halo atom includes, Cl, Br, F, and I.
- Haloalkyl and haloalkoxy are preferably CF 3 and O CF 3 respectively.
- the compounds of formulae (IA) and (IB) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof.
- the invention includes both the individual stereoisomers of the compounds of formulae (IA) and (IB) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (IA) or (IB) or a suitable salt or derivative thereof.
- An individual enantiomer of a compound of formula (IA) or (IB) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.
- the compounds of formulae (IA) and (IB) may also exist in tautomeric forms and the invention includes both mixtures thereof and the individual tautomers.
- radiolabelled derivatives of compounds of formulae (IA) and (IB) which are suitable for biological studies.
- the pharmaceutically or veterinarily acceptable salts of the compounds of formulae (IA) and (IB) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids.
- Compounds of formulae (IA) and (IB) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts.
- a preferred group of compounds of formulae (IA) and (IB) is that wherein R 1 is C 1 to C 2 alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R 2 is C 2 to C 4 alkyl; R 13 is OR 3 or NR 5 R 6 ; R 3 is C 1 to C 4 alkyl optionally substituted with one or two substituents selected from cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR 5 R 6 , phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl; cyclobutyl; 1-methylpiperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R 5 and R 6 are each independently selected from H and C 1 to C 2 alkyl optionally substituted with cyclopropyl or meth
- a more preferred group of compounds of formulae (IA) and (IB) is that wherein R 1 is C 1 to C 2 alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R 2 is C 2 to C 4 alkyl; R 13 is OR 3 ; R 3 is C 1 to C 4 alkyl optionally monosubstituted with cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl; cyclobutyl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 4-R 10 -piperazinyl group optionally in the form of its 4-N-oxide; R 10 is C 1 to C 3 alkyl optionally monosubstituted with OH; and Het is selected from
- Particularly preferred individual compounds of the invention include 3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-yisulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethyl-4-oxidopiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydr
- R 1 is not unsubstituted C 1 alkyl; the optional substituent on the C 1 alkyl group of R 1 is not a substituted phenyl group or a N-linked heterocyclic group; the optional substituent on the C 2 or C 3 alkyl group of R 1 is not phenyl or Het; or wherein R 13 is not NR 5 R 6 ; or wherein the alkyl group of R 3 is not C 5 or C 6 ; or wherein the optional substituent on R 3 is not C 3 to C 5 cycloalkyl; or wherein neither the alkyl or the optional alkoxy substituents on R 3 are terminated by a haloalkyl group; or wherein the C 1 to C 4 alkyl groups of R 5 and R 6 are not substituted by C 3 to C 5 cycloalkyl or C 1 to C 4 alkoxy; or wherein
- the present invention provides processes for the preparation of compounds of formulae (IA) and (IB), their pharmaceutically and veterinarily acceptable salts, and pharmaceutically and veterinarily acceptable solvates of either entity, as illustrated below.
- Illustrative of a protecting group strategy is the route to the 2 1 -(2-hydroxyethoxy) analogue (Example 33), the precursor to which (Example 32) contains benzyl as the alcohol-protecting group.
- vanous standard substituent or functional group interconversions and transformations within certain compounds of formulae (IA) and (IB) will provide other compounds of formulae (IA) and (IB).
- Examples include alkoxide exchange at the 2-position of the 5-(pyridin-3-yl) substituent (see conversions of Example 1 to Examples 4B, 9, 11, 13, 23, 24, 32 and 64, Example 2 to Example 14, Example 20 to Example 21, Example 26 to Examples 29, 65, 66, 67 and 68, Example 35 to Example 36, Example 38 to Examples 39 and 40, and Example 45 to Example 46), amine exchange at the 2-position of the 5-(pyridin-3-yl) substituent (see conversions of Example 78 to Examples 148 and 154) and piperazine and/or pyridine N-oxidation (see conversions of Example 1 to Example 70, Example 28 to Example 71, and Example 4 to Examples 72 and 73).
- a compound of formula (IA) or (IB) may be prepared by alkylation of a compound of formula (IA) or (IB) wherein R 1 is hydrogen and R 2 , R 13 and R 4 are as previously defined for formulae (IA) and (IB), using one or more of a plethora of well-known methods, such as:
- a 10% excess of sodium hydride is added to a solution of the substrate in a suitable solvent, e.g. anhydrous tetrahydrofuran, and the resulting anion treated with about a 10% excess of the required R 1 X.
- a suitable solvent e.g. anhydrous tetrahydrofuran
- a compound of formula (IA) or (IB) wherein R 1 is hydrogen and R 2 , R 13 and R 4 are as previously defined for formulae (IA) and (IB) may be obtained from a compound of formula (IXA) or (IXB) respectively wherein R 1 is hydrogen and R 2 , R 13 and R 4 are as previously defined for formulae (IXA) and (IXB), under the same conditions as those used for the conversion of a compound of formula (IXA) or (IXB) to a compound of formula (IA) or (IB) respectively when R 1 is other than hydrogen, followed by acidification of the reaction mixture to a pH of about 6.
- the amines of formula (III), the 4-aminopyrazole-5-carboxamides of formulae (VIIA) and (VIIB), the carboxylic acids of formulae (VIII) and (X), the nitriles of formula (XIII) and the esters of formula (XVI), when neither commercially available nor subsequently described, can be obtained either by analogy with the processes described in the Preparations section or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
- the pharmaceutically acceptable acid addition salts of the compounds of formulae (IA) and (IB) which contain a basic centre may also be prepared in a conventional manner. For example a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration of by evaporation under vacuum of the reaction solvent.
- Base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (IA) or (IB) with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
- the biological activities of the compounds of the present invention were determined by the following test methods.
- Phosphodiesterase (PDE) inhibitory activity Phosphodiesterase (PDE) inhibitory activity
- the required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W.J. Thompson and M.M. Appleman (Biochem., 1971, 10 , 311).
- the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavemosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina.
- the compounds of formulae (IA) and (IB), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- they are administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
- They can also be injected parenterally, for example intracavemosally, intravenously, intramuscularly or subcutaneously.
- parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
- buccal or sublingual administration they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
- the compounds may also be administered intranasally or formulated for dermal application.
- the daily dosage level of the compounds of formulae (IA) and (IB) and their pharmaceutically acceptable salts and solvates may be from 10 to 500 mg (in single or divided doses).
- tablets or capsules may contain from 5 to 250 mg of active compound for administration singly, or two or more at a time, as appropriate.
- the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
- the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
- compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).
- oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration.
- a preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required.
- the drug may be administered parenterally, sublingually or buccally.
- a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent or carrier.
- a veterinary formulation comprising a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, together with a veterinarily acceptable diluent or carrier.
- the invention also provides a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament.
- the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated.
- a compound of formula (IA) or (IB) or a suitable salt or solvate thereof in the manufacture of a medicament for the treatment of a medical condition in which inhibition of a cGMP PDE5 is desirable.
- the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate containing either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, (e.g.
- post-PTCA post transluminal coronary angioplasty
- chronic asthma bronchitis
- allergic asthma allergic rhinitis
- glaucoma diseases characterised by disorders of gut motility
- IBS irritable bowel syndrome
- Other conditions which may be mentioned include pre-eclampsia, Kawasaki's syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction.
- Particularly preferred conditions include MED and FSD.
- a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate containing either entity for the manufacture of an animal medicament for the curative or prophylactic treatment of male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Pnnzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency (e.g.
- the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.
- a mammal including a human being
- the invention provides a method of treating or preventing male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency (e.g.
- the invention also includes any novel intermediates described herein, for example those of formulae (IIA), (IIB), (IVA), (IVB), (IXA), (IXB), (VA) and (VB).
- Mass spectra (m/z) were recorded using a Fisons Instruments Trio mass spectrometer in the thermospray ionisation mode.
- Room temperature means 20 to 25°C.
- the organic phase was separated, combined with a dichloromethane extract (20ml) of the aqueous phase, dried (MgSO 4 ) and evaporated under reduced pressure.
- the residual yellow foam was purified by column chromatography on silica gel, using dichloromethane: methanol (97:3) as eluant, followed by HPLC using a 5 ⁇ m Spherisorb silica column with water: acetonitrile: diethylamine (50:50:0.1) as eluant at a rate of 1 ml/min, to give the title compound (30mg, 17%) as a white foam.
- Triethylamine (83 ⁇ l, 0.59mmol) and 1-methylpiperazine (36mg, 0.356mmol) were added to a stirred, ice-cooled suspension of the title compound of Preparation 64 (150mg, 0.30mmol) in dichloromethane (10ml) and the reaction mixture stirred for 2 hours at room temperature.
- the crude product was purified by two column chromatography operations on silica gel, using firstly dichloromethane: methanol:0.88 aqueous ammonia (90:10:1) and then a gradient of ethyl acetate: methanol (100:0 to 80:20) as eluants, to yield the title compound as an oil.
- LRMS m/z 568 (M+1) + ; followed by the second title compound (2-isomer; 20mg) as a white solid.
- LRMS m/z 568 (M+1) + .
- the residual yellow oil was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol (90:10 to 80:20), to yield the title compound (33mg, 30%) as a white solid.
- 3-Chlorobenzoic acid (15mg, 0.096mmol) was added to a stirred solution of the title compound of Example 4 (223mg, 0.38mmol) in dichloromethane (3ml) and the mixture stirred at room temperature for 30 minutes.
- 3-Chloroperoxybenzoic acid (132mg, 0.38mmol) was then added and the reaction mixture stirred at room temperature for 14 hours, then partitioned between dichloromethane (5ml) and aqueous sodium bicarbonate solution (5ml). The phases were separated, the aqueous phase extracted with dichloromethane (3x10ml) and the combined organic solutions dried (MgSO 4 ) and evaporated under reduced pressure.
- Example 78 The title compound of Example 78 (400mg, 0.84mmol) was added to a mixture of potassium bis(trimethylsilyl)amide (840mg, 4.2mmol) in ( R )-2-butanol (4ml) and the mixture stirred at 110°C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10ml) and neutralised using 2N hydrochloric acid. This aqueous suspension was extracted with ethyl acetate (3x30ml), the combined organic extracts washed with sodium hydroxide solution (20ml), brine (2x30ml), dried (Na 2 SO 4 ) and evaporated under reduced pressure.
- Example 78 The title compound of Example 78 (100mg, 0.2mmol) and potassium bis(trimethylsilyl)amide (121mg, 0.61mmol) in the intermediate alcohol (1ml), was heated at 110°C for 30 hours, then the reaction cooled and concentrated under reduced pressure.
- the residual brown solid was purified by column chromatography on silica gel using diethylamine: ethyl acetate (5:95) as eluant, and repeated using methanol: ethyl acetate (5:95) as eluant.
- the product was triturated with ether to afford the title compound (7mg, 6%) as a white solid.
- Example 79 The title compound of Example 79 (198mg, 0.42mmol) was added to a solution of potassium bis(trimethylsilyl)amide (415mg, 2.1 mmol) in 1-methoxy-2-propanol (5ml), and the reaction heated at 110°C for 72 hours. The cooled mixture was evaporated under reduced pressure, the residue dissolved in water and neutralised using 2M hydrochloric acid This aqueous solution was extracted with ethyl acetate (3x30ml), the combined organic extracts washed with brine (3x20ml), dried (Na 2 SO 4 ) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100:0 to 97:3), and evaporated from ether to give a white solid.
- the racemic product was purified by chiral HPLC using an AD250 column, and hexane: isopropanol:trifluoroacetic acid (80:20:0.5) as eluant.
- the first enantiomer was redissolved in water, basified using aqueous sodium carbonate solution, and this mixture extracted with ethyl acetate (3x20ml).
- the combined organic extracts were washed with brine (2x20ml) dried (Na 2 SO 4 ) and evaporated under reduced pressure.
- LRMS m/z 520 (M+1) +
- the first enantiomer was partitioned between dichloromethane (20ml) and aqueous sodium carbonate solution (10ml), the phases separated, and the organic layer dried (Na 2 SO 4 ), and evaporated under reduced pressure.
- the product was further purified by column chromatography on silica gel, using ethyl acetate: methanol (95:5) as eluant, to afford the title compound of Example 106 (130mg, 16%, 99.76%ee) as a white foam.
- Example 78 The title compounds were prepared from the title compound of Example 78, and 2-methoxy-1-propanol following a similar procedure to that described for Examples 104 and 105.
- the racemate was further purified by HPLC using an AD250 column and hexane: ethanol:diethylamine (60:40:1) as eluant, to give isomer 1.
- This product was re-purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100:0 to 97:3) and triturated with ether to afford the title compound of Example 108 (8mg, 2%, 82%ee) as a white solid.
- the racemate was prepared (70%) from the title compound of Example 78 and 1-ethoxy-2-propanol, following the procedure described for Examples 104 and 105.
- Example 116 and 117 were obtained as solids, (4%, 99.0%ee) and (2%, 99.0%ee) respectively, from the title compound of Example 78 and 1-(pyridin-2-yl) ethanol (Helv.Chim.Acta., 1955, 38 , 1114), following a similar procedure to that described for Examples 112 and 113, except that hexane: isopropanol: diethylamine (70:30:1) was used as the HPLC eluant.
- Example 124 The title compounds of Examples 128 and 129 were prepared from Example 124 (17%, 99.5%ee) and (15%, 98.6%ee) respectively, following a procedure similar to that described in Examples 106 and 107, except that hexane :isopropanol : diethylamine :trifluoroacetic acid (85:15:0.2:0.3) was used as the HPLC eluant.
- Example 144 (24mg, 11%, 100.0%ee) ⁇ (CDCl 3 ) : 1.02 (3H, t), 1.25 (3H, t), 2.10 (3H, d), 2.40 (2H, q), 2.56 (4H, m), 3.00 (2H, q), 3.13 (4H, m), 3.58 (3H, s), 3.86 (2H, t), 4.77 (2H, t), 5.83 (1H, q), 7.18 (2H, m), 7.60 (1H, m), 8.55 (1H, d), 8.60 (1H, s), 8.96 (1H, s),
- the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 99.6:0.4:0.5) to afford the title compound (50mg, 59%) as a white foam.
- Ammonium nitrate (10.57g, 131mmol) was added portionwise to a stirred, ice-cooled solution of the title compound of Preparation 4 (14.80g, 65.7mmol) in trifluoroacetic anhydride (150ml) and the reaction mixture stirred for 3 hours at room temperature, then carefully poured onto stirred ice (120g). The resulting solution was extracted with dichloromethane (3x150ml), then the combined extracts dried (MgSO 4 ) and evaporated under reduced pressure.
- Triethylamine (3ml, 19mmol) and tetrakis (triphenylphosphine) palladium (0) (260mg, 0.22mmol) were added to a solution of the title compound of Preparation 14 (1.30g, 3mmol) in ethanol (15ml) and the mixture heated under carbon monoxide at 100°C and 1034 kPa (150psi) in a sealed vessel for 18 hours, then allowed to cool. The reaction mixture was filtered and the filtrate evaporated under reduced pressure to provide a yellow solid.
- Oxalyl chloride (0.77ml, 8.85mmol) was added dropwise to a stirred, ice-cooled solution of the title compound of Preparation 23 (1.52g, 4.42mmol) and dimethylformamide (2 drops) in dichloromethane (30ml) and the reaction mixture stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ether and dried under suction to afford the title compound (1.68g, 95%). Found C, 41.51; H, 5.27; N, 10.32. C 14 H 21 Cl 2 N 3 O 4 S; 0.10 CH 2 Cl 2 requires C, 41.73; H, 5.02; N, 10.36%.
- Oxalyl chloride (270 ⁇ l, 3.13mmol) was added dropwise to a stirred, ice-cooled suspension of the title compound of Preparation 25 (390mg, 1.04mmol), dimethylformamide (100 ⁇ l) and dry dichloromethane (20ml), then the reaction mixture stirred for 3 hours at room temperature. The resulting mixture was evaporated under reduced pressure and the residue azeotroped with toluene (2 x 20ml) to give the title compound (390mg, 95%) as a white solid.
- Ethanolic sodium ethoxide solution (21% w/w; 143ml, 0.39mol) was added dropwise to a stirred, ice-cooled solution of diethyl oxalate (59.8ml, 0.44mol) in absolute ethanol (200ml) under nitrogen and the resulting solution stirred for 15 minutes.
- Butan-2-one 39ml, 0.44mol was then added dropwise, the cooling bath removed, the reaction mixture stirred for 18 hours at room temperature and then for 6 hours at 40°C, then the cooling bath reintroduced.
- Aqueous sodium hydroxide solution (10M; 100ml, 1.0mol) was added dropwise to a stirred suspension of the title compound of Preparation 30 (66.0g, 0.39mol) in methanol (400ml) and the resulting solution heated under reflux for 4 hours.
- the cool reaction mixture was concentrated under reduced pressure to ca . 200ml, diluted with water (200ml) and this mixture washed with toluene (3x100ml).
- the resulting aqueous phase was acidified with concentrated hydrochloric acid to pH 4 and the white precipitate collected and dried by suction to provide the title compound (34.1g).
- Fuming sulphuric acid (17.8ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0ml), the resulting solution heated to 50°C, then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984, 32 , 1568; 16.4g, 0.106mol) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60°C.
- the resulting solution was heated for 18 hours at 60°C, allowed to cool, then poured onto ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4g), m.p. 170-172°C.
- Oxalyl chloride (2.73ml, 31mmol) was added dropwise to a stirred suspension of the title compound of Preparation 8 (3.31g, 15.7mmol) in dichloromethane (50ml), followed by dimethylformamide (2 drops), and the reaction mixture stirred at room temperature for 3 hours. The resulting mixture was evaporated under reduced pressure and the residue azeotroped with hexane to give a white solid.
- Oxalyl chloride (122 ⁇ l, 5.6mmol) was added dropwise to a stirred solution of the title compound of Preparation 79 (478mg, 1.4mmol) and dimethylformamide (3 drops) in dichloromethane (10ml) and the reaction mixture stirred at room temperature for 18 hours, then evaporated under reduced pressure. The residue was azeotroped with dichloromethane (3x10ml), then added to a stirred, ice-cooled solution of the title compound of Preparation 41 (360mg, 1.4mmol) in pyridine (10ml) and the reaction mixture stirred at room temperature for 18 hours, then evaporated under reduced pressure.
- Zinc chloride (820mg, 6mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60mmol) and 3-methylpyridazine (2.83g, 30mmol) and the resulting mixture heated for 20 hours at 150°C.
- the cool reaction mixture was partitioned between dichloromethane (40ml) and 2M aqueous sodium hydroxide solution (20ml), then the organic phase separated, combined with a dichloromethane extract (80ml) of the aqueous phase, dried (Na 2 SO 4 ) and evaporated under reduced pressure.
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Claims (4)
- Verbindung der Formel (X) worin
R13 OR3 darstellt, worin R3 C1-C4-Alkyl, gegebenenfalls substituiert mit einem oder zwei Substituenten, ausgewählt aus OH, C1-C4-Alkoxy, Benzyloxy, NR5R6, Phenyl, Furanyl und Pyridinyl; C3-C6-Cycloalkyl; 1-(C1-C4-Alkyl)piperidinyl; Tetrahydrofuranyl oder Tetrahydropyranyl
R4 SO2NR7R8 darstellt;
R5 und R6 jeweils unabhängig aus H und C1-C4-Alkyl,
ausgewählt sind oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine Pyrrolidinyl-, Piperidinyl- oder Morpholinylgruppe darstellen;
R7 und R8 zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine 4-R10-Piperazinylgruppe, gegebenenfalls substituiert mit einer oder zwei C1-C4-Alkylgruppen, und gegebenenfalls in Form ihres 4-N-Oxids, bilden; und
R10 H; C1-C4-Alkyl, gegebenenfalls substituiert mit einem oder zwei Substituenten, ausgewählt aus OH, NR5R6, CONR5R6, Phenyl, gegebenenfalls substituiert mit C1-C4-Alkoxy, Benzodioxolyl und Benzodioxanyl; C3-C6-Alkenyl; Pyridinyl oder Pyrimidinyl darstellt; oder ein Salz einer solchen Verbindung, oder ein Saurechloridderivat von einer solchen Verbindung. - Verbindung nach Anspruch 1, worin R13 OR3 darstellt, R3 C1-C4-Alkyl, gegebenenfalls monosubstituiert mit OH, Methoxy, Ethoxy, Phenyl, Furan-3-yl oder Pyridin-2-yl; Cyclobutyl; Tetrahydrofuran-3-yl oder Tetrahydropyran-4-yl, darstellt; R7 und R8 zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine 4-R10-Piperazinylgruppe, gegebenenfalls in Form ihres 4-N-Oxids, bilden; und R10 C1-C3-Alkyl, gegebenenfalls monosubstituiert mit OH, darstellt.
- Verbindung nach Anspruch 1 oder 2, ausgewählt aus:2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-carbonsäure;2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-carbonsäure-Natriumsalz;4-(4-Ethylpiperazin-1-ylsulfonyl)-2-(2-methoxyethoxy)pyridin-3-carbonsäure-Hydrochlorid;2-(2-Ethoxyethoxy)-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-carbonsäure-Hydrochlorid;5-(4-Ethylpiperazin-1-ylsulfonyl)-2-(3-methoxyprop-1-oxy)pyridin-3-carbonsäure-Hydrochlorid;2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-pyridin-3-carbonsäure-Hydrochlorid; und5-(4-Ethylpiperazin-1-ylsulfonyl)-2-(2-methoxyethoxy)-pyridin-3-carbonsaure-Hydrochlorid.
- 2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-pyridin-3-carbonsäure nach Anspruch 1 oder 2.
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US6723719B1 (en) | 1997-04-25 | 2004-04-20 | Pfizer Inc | Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′—monophosphate phosphodiesterase (cGMP PDE5) for the treatment of sexual dysfunction |
GB9722520D0 (en) | 1997-10-24 | 1997-12-24 | Pfizer Ltd | Compounds |
EP1371647B1 (de) * | 1998-04-20 | 2005-07-13 | Pfizer Inc. | Pyridin-3-carbonsäurederivate und ihre Verwendung als Zwischenprodukte |
GB9823101D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
GB9823102D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
GB9823103D0 (en) * | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
US6242444B1 (en) | 1999-06-04 | 2001-06-05 | The Jordanian Pharmaceutical Manufacturing And Medical Equipment Co., Ltd. | Compounds and pharmaceutical compositions containing the same |
US7235625B2 (en) | 1999-06-29 | 2007-06-26 | Palatin Technologies, Inc. | Multiple agent therapy for sexual dysfunction |
TWI265925B (en) * | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
GB9923968D0 (en) * | 1999-10-11 | 1999-12-15 | Pfizer Ltd | Therapeutic agents |
US6350751B1 (en) | 1999-10-11 | 2002-02-26 | Pfizer Inc. | Therapeutic agents |
NZ517324A (en) * | 1999-10-11 | 2003-09-26 | Pfizer | 5-(2-substituted-5-heterocyclylsulphonylpyrid-3-YL)- dihydropyrazolo[4,3-d]pyrimidin-7-ones as phosphodiesterase inhibitors |
GB9924020D0 (en) | 1999-10-11 | 1999-12-15 | Pfizer Ltd | Pharmaceutically active compounds |
YU59100A (sh) * | 1999-10-11 | 2003-10-31 | Pfizer Inc. | Postupak za dobijanje pirazolo (4,3-d) pirimidin-7-ona-3-piridilsulfonil jedinjenja i njihova intermedijera |
IL139073A0 (en) * | 1999-10-21 | 2001-11-25 | Pfizer | Treatment of neuropathy |
TW200400821A (en) * | 1999-11-02 | 2004-01-16 | Pfizer | Pharmaceutical composition (II) useful for treating or preventing pulmonary hypertension in a patient |
GB0000561D0 (en) * | 2000-01-11 | 2000-03-01 | Pfizer Ltd | Treatment of diabetic ulcers |
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